Progress in the art of medical organ transplant has increased the demand for viable organs, tissues and cells from donors. Given the stringent requirements for tissue and blood type matching, and the limited sources for donations, the supply of available hearts, livers, lungs, kidneys, etc. is generally substantially less than the number of patients waiting for a life-extending transplant. Thus, there remains an ongoing need to optimize the limited supply of donated organs. One way that the art has sought to maximize the availability of donated organs is by improving the preservation of organs after donation.
Generally, current donor organ preservation protocols do not attempt to recreate an in vivo-like physiologic state for organs separated from a normal blood supply. Instead, they utilize hypothermic (below 20° C. and typically at about 4° C.) and storage in an osmotically neutral, crystalloid solution. The most common solutions for heart preservation are The University of Wisconsin Solution (UW), St. Thomas Solution, and the Stanford University Solution (SU).
This and other current methods for preserving viability of an organ that has been separated from its usual nutrient sources, e.g., the blood circulation of a living animal or person, depend on contacting and/or perfusing the organ with a supportive solution designed to provide pH buffering, osmotic balance and/or some minimal nutritional support, e.g., in the form of glucose and a limited set of other basic nutrients. This approach is typically combined with reduction in organ temperature to just above the freezing point of water. This is intended to reduce the metabolic rate of organ tissues, thus slowing the consumption of nutrients and the production of waste products. These art-known preservative solutions included, for example, isotonic saline solutions, that may contain, in various proportions, salts, sugars, osmotic agents, local anesthetic, buffers, and other such agents, as described, simply by way of example, by Berdyaev et al., U.S. Pat. No. 5,432,053; Belzer et al., and the product ViaSpan®, described by U.S. Pat. Nos. 4,798,824, 4,879,283; and 4,873,230; Taylor, U.S. Pat. No. 5,405,742; Dohi et al., U.S. Pat. No. 5,565,317; Stern et al., U.S. Pat. Nos. 5,370,989 and 5,552,267. The ViaSpan® product data sheet describes the product as a sterile, non-pyrogenic solution for hypothermic flushing and storage of organs. The solution has a approximate calculated osmolarity of 320 mOsM, a sodium concentration of 29 mEq/L, a potassium concentration of 125 mEq/L, and a pH of 7.4.
Preservative solutions that contain pyruvate, inorganic salts supporting cell membrane potential and albumin or fetal calf serum, are described in U.S. Pat. No. 5,066,578 while U.S. Pat. Nos. 6,495,532 and 6,004,579, describe organ preservative composition that includes one or more phosphatidic acids or sugars, and lysophosphotidic acids or sugars, together with enhancers such as albumen, optionally delivered in liposomal compositions.
The storage and transport of organs supported in this way, in hypothermic storage remains limited in time. Given the ongoing shortage of donated organs, there still remains a longstanding need to extend the time for storage or transport before reimplantation. It has been hypothesized that one important cause of the short storage time for reimplantation, is damage incurred during cold storage, followed by tissue injury that occurs during warming and repurfusion with blood of the transplant recipient.
It has been proposed to remedy this problem by employing a liposome composition that includes various phospolipids to prevent apoptosis (programmed cell death) of cells or organ tissues in storage, as described, e.g., by U.S. Pat. Nos. 6,004,579 and 6,495,532. However, this proposal has not produced the sought-after improvements in viability and longevity of organs in storage. It also suffers from a number of drawbacks, including undesirable levels of uptake of phospholipids into tissues.
As can be readily appreciated, there remains a longstanding need in the art for compositions and methods for the improved preservation of viable organs, tissues and even cells for prolonged periods away from normal circulatory support, both in vivo and in vitro, that are optionally combined with suitable oxygen carriers for enhanced maintenance of tissue and cell viability.